A
2A adenosine receptors are highly expressed in the striatum where they modulate dopaminergic activity. The role of A
2A receptors in psychostimulant action is less well understood because of the lack of A
2A-selective compounds with access to the central nervous system. To investigate the A
2A adenosinergic regulation of psychostimulant responses, we examined the consequences of genetic deletion of A
2A receptors on psychostimulant-induced behavioral responses. The extent of dopaminergic innervation and expression of dopamine receptors in the striatum were indistinguishable between A
2A receptor knockout and wild-type mice. However, locomotor responses to amphetamine and cocaine were attenuated in A
2A knockout mice. In contrast, D
1-like receptor agonists SKF81
297 and SKF38393 produced identical locomotor stimulation and grooming, respectively, in wild-type and A
2A knockout mice. Similarly, the D
2-like agonist quinpirole produced motor-depression and stereotypy that were indistinguishable between A
2A knockout and wild-type mice. Furthermore, attenuated amphetamine- (but not SKF81
297-) induced locomotion was observed in pure 1
29-Steel as well as hybrid 1
29-Steel×C
57BL/6 mice, confirming A
2A receptor deficiency (and not genetic background) as the cause of the blunted psychostimulant responses in A
2A knockout mice.
These results demonstrate that A2A receptor deficiency selectively attenuates psychostimulant-induced behavioral responses and support an important role for the A2A receptor in modulating psychostimulant effects.